Process for the preparation of 6-methyl-5-ene-steroids



Unite tates PROCESS FOR THE PREPARATION OF G-METHYL-S-ENE-STEROIDS David Neville Kirk, Vladimir Petrow, and Marianne Helen Thomson, London, England, assignors to The British Drug Houses Limited, London, England, a ,British company No Drawing. Filed Jan. 3, 1959, Ser. No. 785,581

Claims priority, application Great Britain Jan. 16, 1958 11 Claims. (21. 260-23955) a method for the preparation of 6-methyl derivatives of diosgenin, 3132205 dihydroxypregn 5 ene, 3 )9: 17fl-dihydroxyandrost-S-ene, cholesterol and stigmasterol.

6-methyl-diosgenin 1 is a starting material for the preparation of G-methyl steroid hormones which frequently show significantly greater biological activity than the unmethylated compounds. Thus it can be degraded by methods applied by prior art to diosgenin to yield 6-rnethylpregnadieneolone, -rnethylpregneualone, 6-methylprogesterone and G-methyl-dehydroisoandrosterone which can then be converted by conventional methods to such biologically active compounds as 6a-methylprogesterone, 6-methyla'ndrostanolone, and 6a-n1ethylethisterone, which are superior to the corresponding o-de srnethyl' compounds. 6-methyl-3B:ZOfi-dihydrOXypregn-S-ene Mo 1 om is an intermediate for 6-rnethyl progresterone into which it may be converted by Oppenauer oxidationand which is itself progrestational in effect and is useful for preparation of 6-rnethyl corticoid hormones.

2,981,732 Patented Apr. 25, 1961 "ice 6-methyl-3fi: 17 p-dihydroxyandrost- -ene can be converted to progestationally active substances such as 6u-methylethisterone (fim-methyl-flfi-hydroxy- 17a-pregn-4-en-20-yne-3-one) and 6a:21--dimethylethis* terone, 6a 21-dirnethyl-l7[3-hydroxy-17a-pregn-4-en-20- yne-3-one) by the application of conventional methods previously employed in the fi-desmethyl series, the resulting products being superior in biological activity to the corresponding 6-desmethyl compounds. V 6-methylchlocsterol and 6-methylstigma sterol Me /CH:

CH Me I CH-CH CHgMe Me are general starting materials for 6-methyl hormones.

6-methyl-3/3:ZOfi-dihydroXy regn-S-ene and 6-methyl stigma sterolvand their 3fi-acyl, and 3/3-aroyl derivatives are new chemical. compounds. 1 a

According to the present invention there is provide a process for the preparation of 3[3-acyloxy-, and 3;?- aroylo'xy6-rnethyl-A5-steroids from the corresponding 3}8;5oz-dihydroxy, 3,3-acyloxy 5a-hydroxy or 3fl-aroyloxy-Swhydoxy-6fi-methylsteroids, .which' process. comprises treating the appropriate 3 B:5u-.dihydroxy.-6fi methyl-steroid, or the corresponding 3fi-acyloxy or Bil-aroyloxy derivative having the formula where R is hydrogen or an acyl or aroyl group containing up to 10 carbon atoms with an acidic catalysts in an acylating agent.

The resulting 35-acyloxy. or 3fi-aroyloxy-6-methyl-A steroid may be converted into the Bp-hydroXy-G-methyI- 3 A -steroid by methods well known to those skilled in the art, such as alkaline hydrolysis.

The acidic catalyst in the acylating agent may be mixed with a diluent such as. the acid corresponding to the acylating agent.

Acetic anhydride is the preferred acylating agent but other anyhdrides such for example as propionic anhydride and succinic anhydride may be used; isopropenyl acetate and acid chlorides such as benzoyl chloride and acetyl chloride may also be used.

Acetic acid is the preferred diluent, but other diluents such as ethylene dichloride or benzene may be employed.

Perchloric acid is the preferred acidic catalyst but toluene-p-sulphonic acid, as well as Lewis acids such as boron trifiuoride, zinc chloride and aluminium chloride may also be employed.

The reaction may be carried out at any temperature between the freezing-point of the solution and 100 C. and is generally most conveniently performed at or about room temperature, though a higher temperature may be desirable when a Lewis acid is used. The product may be isolated by usual procedures such as, for example, by pouring the reaction mixture into water and collecting the precipitated solids, or by extraction with a suitable solvent such as ether or benzene.

Following is a description by way of example of methods of carrying the invention into effect.

Example 1 3B:5-dihydroxy-6p-methyl-5a:25D-spirostane (2 g.)

treated as in Example 1 gave 3fl-acetoxy-6-methyl-25D- spirost-S-ene identical with the previous sample.

Example 3 The reaction was carried out as in Example 1 only acetyl chloride was used instead of acetic anhydride,

with identical results.

Example 4 The reaction was carried out as in Example 1, using formic acid instead of acetic acid, with identical results.

Example 5 Propionic acid and anhydride were. substituted for ace- -tic acid and anhydride in Example 1. 3fi-acetOxy-6- methyl-25D-spirost-5ene, identical with previous sam- -ples, was obtained.

Example 6 The reaction was carried out as under Example 1, us- .ing succininanhydride instead of acetic anhydride, with identical results.

Example 7 3,8:5-dihydroxy 6fi-methyl-5a:25D-spirostane (10 g.) suspended in acetic anhydride (100 ml.) was stirred and treated with 72% perchloric acid (2 drops) for 1 /2 hours after which the crystalline solids were collected and washed with methanol, then purified from ethyl acetate to give 3 8-acetoxy-6-methyl-25D-spirost-S-ene identical with previous samples.

Example 8 3&acetoxy-5-hydroxy-fifl-methyl-Sa:25D spirostane (2 g.) suspended in isopropenyl acetate (25 ml.) wastreated with 72% perchloric acid (2 drops). After /2 hour ether was added and the solution was washed neutral and the solvents removed. 3e-acetoxy-6-methyI-ZSD-spirost- S-ene, identical with previous samples, was obtained after purification from ethyl acetate.

Example 9 3fl-acetoxy-5-hydroxy-6fi-methyl-5az25D-spirostane (2 g.) suspended in acetic acid (40 ml.) and acetic anhydride (5 g.) was treated with toluene-p-sulphonic acid (0.5 g.) and stirred for 4 hours. The product, isolated as in Example 1, was 318-acetoxy-Gmethyl-ZSD-spirost- S-ene, identical with previous samples.

Example 10 Boron trifiuoride etherate (,1 ml.) was substituted for toluene-p-sulphonic acid (see Example 9), and the mixture was stirred for 24 hours. The product was 3p-acetoxy-6methyl-ZSD-spirost-S-ene, identical with previous samples.

Example 11 35:50:20B-trihydroxy-6,8-methylpregnane (1.4 g.), prepared as disclosed in copending application Ser. No.

587,447, filed May28, 1956, in acetic acid (28 ml.) and acetic anhydride (7 ml.) was treated with 72% perchloride acid (0.1 ml.) for 20 minutes, when the solution was poured into water; The precipitated solids were collected and purified from aqueous methanol (75%) to give 3B:ZOfl-diacetoxy-6-methylpregn-5-ene in M.P. 155 C., [0.1 45 (c. 0.36 in 'chloroform).

Saponification of the foregoing 3:20-diacetate (0.4 g.) by heating for 45 minutes with potassium hydroxide (0.4

g.) in aqueous methanol (15 ml.) gave 3;8-20B-dihy droxy-6-methyl-pregn-S-ene, which separated from acetone/hexane (1:2) flakes, M.P. 207 to 208 (3., [@1324 74 (c. 0.42 in chloroform).

Example 13 3,3-acetoxy-5-hydroxy-6,3-methyl-5a:ZSD-spirostane (2 g.) suspended in acetic acid (40 ml.) and benzoyl chlo- .ride (2 ml.) Was treated with 72% perchloride acid (0.1

ml.) for 2 hours. Precipitation in water and purificatron from ethyl acetate gave 3 3-acetoxy-6-methyl-25D- sprrost-S-ene, identical with previous samples.

Example 14 Octanoic anhydride (5 ml.) was substituted for benzoyl chloride in the previous example and the mixture was left at room temperature for 6 hours, then poured .into

a solution of sodium hydroxide (40 ml.) in water (1 litre). The solids were collected and purified. from ethyl acetate to give BB-acetoxy-G-methyl-ZSDspirost-S- ene, identical with previous'sarnples.

Example 15 residue from chloroform: ethanol (1:4) gave Sfl-acetoxy- 6rnethyl-ZSD-spirost-Sene identical with previous samples.

Example 16 lz2-dichloroethane was substituted for benzene in EX- ample 15, with the same result.

Example 17 3p:S-dihydroxy-Gfi-methyl-Sa:25D-spirostane (2 g.) suspended in anhydrous formic acid (65 ml.) was treated with 72% perchloric acid (1 drop). The solid dissolved, and after a few minutes crystalline material separated. This was collected on a filter and purified from chloroformzethanol (1:5) to give SB-formoxy-G-methyl-ZSD- spirost-S-ene in flakes, M.P. 214 to 216 C., [011 -126 (c. 0.33 in chloroform).

Example 18 3fi-acetoxy-5-hydroxy-6 8-methyl-5a:25D-spirostane (2 g.) in acetic acid (40 ml.) and acetic anhydride (10 ml.) containing anhydrous zinc chloride (1 g.) was heated to 70 C. for 5 hours then poured into water. The solids were collected and purified from ethyl acetate to give 3/3-acetoxy-6-methyl-2SD-spirost-S-ene, identical with previous samples.

Example 20 Anhydrous aluminum chloride (1 g.) was substituted for zinc chloride in the previous example, with similar results.

Example 21 3/3-benzoyloxy-5-hydroxy-6B-methyl-5a:5D spirostane (1 g.) in acetic acid (40 ml.) and acetic anhydride (5 ml.) was stirred with 72% perchloric acid (2 drops) for 1 hour and then poured into water. The precipitated solids were purified from methylene chloride:acetone (1:2) to give 3,8 benzoyloxy 6 methyl 25D-spirost-5-ene in plates M.P. 188 to 192 C., 80.2 (c. 0.474 in chloroform).

Example 22 3,8:e-dihydroxy-6fi-methylchloestane (2 g.) in acetic acid (40 ml.) and acetic anhydride (5 ml.) was stirred with 72% perchloric acid (0.2 ml.) for 1 hour, then poured into water. The solids were collected and purified from methanol to give 3 S-acetoxy-6-methylcholest-5- ene in flakes, M.P. 114 to 116 C., [M 50 (c. 0.24 in chloroform).

Example 23 3l3-5a-DIHYDROXY-GB-METHYLSTIGMAST-22-ENE Stigmasteryl acetate a-epoxide (Fernholz, Ann., 1934, 508, 315) in benzene (600 ml.) was added to a Grignard reagent prepared from magnesium (19.5 g.), methyl iodide (50 ml.) and ether (300 ml.). The mixture was distilled until a vapour-temperature of 70 C. was reached, whereafter the mixture was refiux for 2% hours, cooled, and the complex decomposed by the addition of'aqueous ammonium chloride. The organic layer was washed with dilute mineral acid, then with water, dried, and the solvents removed under reduced pressure. The residue was crystallised from ethanol to give plates of 3fl:5mdihydroxy-6/3-methylstigmast-22-ene, M.P. 170 C., 28 (c. 0.67 in chloroform).

3B:5a-dihydroxy-6fl-methylstigmast-22-ene M.P. 170 C., [711 28 (4 g.) suspended in a mixture of acetic acid (50 ml.) and acetic anhydried (8 ml.) was treated with 3 drops of 72% perchloric acid. The mixture was stirred for 30 minutes, and the crystalline deposit collected and purified from ethanol. 6fi-methylstigmasteryl acetate separated in flat needles, M.P. 105 to 107 C. [041 -59 (c. 0.93 in chloroform).

Saponification of the foregoing acetate by the process of Example 13, and purification from ethanol, gave 6- methylstigmasterol, M.P. 133 to 134 C., [(11 '--49 (c. 0.51 in chloroform).

We claim:

1. A process for the preparation of 3,8-acyloxy-6-methyl-A -steroids which process comprises reacting the corresponding 5a-hydroxy-6-methyl steroid having in rings A and B the formula toluene-p-sulphonic acid, and a Lewis acid in an acylating agent containing a residue of a carboxylic acid having up to 10 carbon atoms.

2. A process as claimed in claim 1 wherein said acidic catalyst is perchloric acid.

3. A process as claimed in claim 1 wherein said acidic catalyst is toluene-p-sulphonic acid.

4. A process as claimed in claim 1 wherein said acylating agent is acetic anhydride.

5. A process as claimed in claim 1 wherein said acylating agent is succinic anhydride.

6. A process as claimed in claim 1 wherein said acylating agent is isopropenyl acetate.

7. A process as claimed in claim 1 wherein said acylating agent is benzoyl chloride.

8. A process as claimed in claim 1 wherein said acidic Catalyst is mixed with a diluent comprising the acid corresponding to said acylating agent.

9. A process as claimed in claim 8 wherein said diluent is acetic acid.

10. A process as claimed in claim 8 wherein said diluent is ethylene dichloride.

11. A process as claimed in claim 8 wherein said diluent is benzene.

References Cited in the file of this patent UNITED STATES PATENTS Miescher et al. Apr. 6, 1954 Brown May 31, 1955 OTHER REFERENCES Zhurnal Obshchei Khimii: vol. 9, pp. 436-441 (1939).

Fieser and Fieser: Natural Products Related to Phenanthrene, 3rd edition 1949, pp. 386-7.

Dans et al.: Chem. Abst., vol. 46, 2557 (1952).

Fieser and Fieser: Steroids, 1959, p. 692. 

1. A PROCESS FOR THE PREPARATION OF 3B-ACYLOXY-6-METHYL-$5-STEROIDS WHICH PROCESS COMPRISES REACTING THE CORRESPONDING 5A-HYDROXY-6-METHYL STEROID HAVING IN RINGS A AND B THE FORMULA 